Over 6 million Americans are diagnosed annually with musculoskeletal disease, which is a major cause of work disability. Annual costs associated with treatment and care of musculoskeletal disease is in the tens of billions of dollars. Muscle degeneration and impairment in such disease may be stemming from various causes, including tissue ischemia, severe injury, advanced age, and muscular dystrophy resulting form genetic defects as well as major diseases such as cancer or kidney failure.
Current key therapeutic approaches and standards of care are typically limited to physiotherapeutic rehabilitation, pain management and anti-inflammatory medications. Lately, there has been an increased interest in developing new interventions focused directly on muscle regeneration. For example, some promise was shown by using cell therapies and related muscle progenitor cells injected directly or as a part of the polymer scaffold (Levenberg et al. 2005). However, this approach is limited by poor integration of the transplanted cells and their low survival.
Growth factors have also been extensively explored in context of ischemic vascular regeneration (Silva et al., 2007), and more recently extended to muscular regeneration (Messina et al., 2007; Kärkkäinen et al., 2009). It is notable that most of the work was done with a vascular endothelial growth factor VEGF, a well-known proangiogenic regulator and thus it was challenging to separate angiogenic contributions from direct effects on muscle development and evolution of the related progenitor cells population. However, in a recent article Borselli et al. (Borselli et al., 2010) showed a synergistic effect of VEGF and an insulin growth factor IGF-1 that binds to type I receptors and may activate several intracellular signaling pathways including the MAP kinase, PI3-K, and the calcium-calmodulin-dependent protein kinase pathway; and therefore lead to the activation and proliferation of the satellite cells, their terminal myogenic differentiation, increased protein synthesis, and myofiber survival. In this respect, it was shown that a sustained-release alginate formulation of both singular agents and their combination was much more effective than bolus administration.
Additional therapeutic approaches have looked into heat shock protein 70 (HSP70), one of several proteins in the general class of heat shock proteins (HSPs). HSP70 has been implicated in many processes including folding and unfolding of nascent proteins, activation of a multi-enzymatic complex, and protein transport. Additionally, HSPs are important for the maintenance of cell integrity during normal growth as well as during pathophysiological conditions (Vigh et al. 1997). It has been shown that tissue injury, whether caused by surgery, trauma or disease, results in the induction of heat shock/stress proteins. An inducible form of the 70 kDa heat shock protein family HSP72 has been detected intra- and extra-cellularly in different organs, including skeletal muscles in response to exercise.
The biological significance of these processes appears to be related: to aid cell survival and chaperone misfolded and denatured proteins. As molecular chaperones, HSPs are also fundamental in facilitating cellular remodeling processes inherent to the training response (Morton et al. 2009; Whitman et al. 2008). Moreover, the beneficial effects of HSPs have been implicated in a number of different diseases such as diabetes; wound healing (Atalay et al. Curr. Pep. Prot. Sc. 2009; 10:85); cancer (Ciocca et al., Stress Cell Chap. 2005; 10:86; Guzhova et al. Tsitologia 2005, 47:187); sepsis (McConnell et al.; J. Immun. 2011; 186:3718; Kustanova et al. Cell Stress Chap. 2006; 11:276); cardiac injury (Knowlton et al. Am. J. Physiol. Heart Cir. Physiol. 2001; 280:H455); muscular injury and degeneration; recovery from physical and exercise stress (Morton et al. Sports Med. 2009; 39(8):643); neuro-degeneration including Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis (Turturici et al., Biochem. Res. Int. 2011); spinal cord injury (Reddy et al. Neurosurg. Focus 2008, 25(5):1); traumatic brain injury; stroke; eye neurodegenerative diseases including glaucoma and macular degeneration (Levin, Surv. Ophthalm. 2003; 48:S21); and epilepsy (Ekimova et al. J. Neurochem. 2010; 115:1035).
At the same time, it has been found that patients with chronic fatigue syndrome (CFS) present an accentuated exercise-induced oxidative stress. Compared with controls, resting CFS patients had low levels of HSP70 and delayed and marked reduction of HSP70 levels in response to maximal exercise (Jammes et al. 2009). In this regard, HSP70 has been implied as a main mediator of the phytoadaptogens such as Rhodiola rosea and Eleutheroccoccus senticosus that improve attention, cognitive function and mental performance in fatigue and chronic fatigue syndrome as well as increase endurance. HSP70 inhibits the expression of the NO synthase II and affects the levels of circulating cortisol via direct interaction with glucocorticoid receptors and JNK pathway. Consequently, prevention of the stress-induced NO and associated decrease in ATP production result in increased performance and endurance (Panossian et al. 2009). Additionally, in HSP70 inhibition (by siRNA interference and a small molecule, N-formyl-3,4-methylenedioxy-benzylidene-butyrolactam, KNK-437) models of vascular insufficiency (Shiota et al. 2010), the lack of HSP70 was linked to disruption of the VEGF-related pathways and Akt activation specifically.
In an effort to capitalize on the involvement of HSP70 in many of these disorders or conditions, several patent applications have reported the utility of HSPs in relation to the recovery from injury (Slepian, U.S. Pat. No. 5,914,345; Srivastava, US Patent Application US 2003/0012793). Additional applications have focused on compounds that induce HSP70, such as geranylgeranylacetone, which have been described to protect subjects from the effect of ischemic-reperfusion injury (Takahashi N, U.S. Pat. No. 6,846,845 B2). Moreover, BGP-15, a pharmacological inducer of Hsp72 (currently in clinical trials for diabetes), has been shown to improve muscle architecture, strength, and contractile function in severely affected diaphragm muscles in two dystrophic mice models relevant to Duchenne muscular dystrophy (Gehrig et al., 2012).
Although evidence has suggested the role of HSP70 in certain indications, current treatments that have adopted strategies to control in vivo HSP70 production have not met the need in this arena. As such, there is strong need for novel therapies that address this current demand.